The present invention relates to compositions and methods for providing nutrition. More specifically the present invention relates to compositions and methods for the nutritional management of nitrogen metabolism.
In the quest for sufficient food energy to meet caloric requirements, animals ingest more nitrogen, largely as amino acids, than they require. Accordingly, the excess nitrogen ingested must be excreted in some form. Through the action of a series of related enzymes called transaminasis, virtually all metabolic nitrogen can be transferred to .alpha.-ketoglutaric acid to form glutamic acid. Under the influence of glutamic dehydrogenase, glutamic acid may be oxidized by the coenzyme diphosphopyridine nucleotide (DPN) with the reformation of .alpha.-ketoglutaric acid plus ammonia.
Since the resulting ammonia produced from the oxidation of glutamic acid is toxic if it exceeds "normal" levels, the body systems of animals work to convert the ammonia into urea to maintain ammonia levels at acceptable levels. The liver is the major site where ammonia is detoxified, by the concurring interaction of both the urea cycle and the glutamine/glutamate cycle.
To accomplish the conversion of ammonia to urea, advantage is taken of the enzymically catalyzed metabolic sequence by which the amino acid arginine is synthesized from ornithine, a sequence common to almost all living forms. Arginase catalyzes the hydrolysis of arginine to urea plus ornithine, which is then available for recycling.
If the liver is compromised in its ability to detoxify ammonia, due to systemic overproduction, hepatic disease, disordered glutamine/glutamate metabolism, and acidosis, ammonia levels can increase to unacceptable levels. A common response to prevent excess ammonia in these states is to terminate all nitrogen-containing feeds. However, this is clinically unacceptable.
An alternate maneuver is to provide a nutritional source (especially the protein fraction) that produces minimal ammonia. This approach is the basis for a number of commercial products, that are designed to provide nutritional support to hepatic patients. With such products, the profile of amino acids is designed to minimize the content of those amino acids that are the most potent in terms of yielding free ammonia upon metabolism commonly known as "ammonotelic" amine acids. The ammonotelic amino acids (all in L-forms) are: glycine; threonine; serine; histidine; tryptophan; glutamine; and methionine. Limiting the production of ammonotelic amino acids minimizes the exogenous provision of a source of ammonia.
An adjunctive nutritional strategy to enhance the detoxification of ammonia is to provide generous amounts of arginine. Arginine is well known to be a major and effective "stimulator" of urea cycle function, and has been so used clinically.
Certain patients may have a relatively impaired ability to efficiently detoxify ammonia. These patients include those having: severe trauma and/or sepsis; renal disease; and hepatic disease. Providing diets that are low in ammonotelic amino acids but contain generous amounts of arginine may effectively manage "nitrogen waste" problems in such patients.
However, high levels of dietary arginine can be deleterious in certain clinical conditions. Arginine, in addition to its role in the urea cycle, creatinine and protein synthesis, is a precursor molecule for nitric oxide production. Inflammatory reactions to bacterial infection, severe trauma or burns trigger the release of "inflammatory mediators," such as leukotrienes, complement, and cytokines (e.g. , interleukin-2, tumor necrosis factor). These inflammatory mediators in turn induce the release of nitric oxide.
Nitric oxide is a potent vasodilator and generator of free oxygen radicals. The result of nitric oxide action is unresponsive hypotension, oxidative tissue damage, multiple organ dysfunction syndrome and septic shock thus, arginine can worse the condition of such patients.
Therefore, a need exists for a nutritional composition that can be administered to patients with actual or potential increased ammonia levels and can provide nutritional support to the patient without generating excess nitric oxide in the patient.